Intermediates for the synthesis of riboflavin and process for producing such intermediates



Patented Feb. 20, 1945 UNITED STATES. PATENT OFFICE amass BIBOFLAVIN ANDPROCESS FOR PRODUC- lNG SUCH INTERMEDIATE-S Max 'lishler, Railway, N.:4, and mm w. Wellman, Cleveland Heights, Ohio, usiznors to Merck a co.Inc., III, N. 1., a corporation of New Jersey I No Drawing. ApplicationSeptember 5, 1942, Se- I181 No. 457,466. In Canada January 13 1.941

' 1s am. (or. 260-205) This invention relates generall to themanufeature of vitamin substances and in a more particular sense tointermediates useful in the synthesis of riboflavin, together withprocesses for manufacturing the same.

The present invention is concerned with the synthesis of1-ribitylamino-2-arylazo-4,5-dimethylv benzene andl-ribitylamino-2-para-sub-' stituted-arylazo-4,5-dimethyl benzencompounds which are useful as intermediates in the synthesis 01'riboflavin. The invention is pa'rticuv iarly concerned with the2-phenyiazo compound which can be condensed with barbituric acid to formriboflavin.

. in accordance with the present invention, an aryl-dlazonium-haiide ora para-substituted- 165 gm. of sodium nitrite in 201cc. of water areadded rather rapidly, and the mixture is allowed tostand for 1 /2 hours.During this time, nearly all of the nitroaniline hydrochloride reactsand passes into solution. The excess of nitrous acid is then destroyedby adding urea, the mixture is filtered from small amounts of insolublema terial, and the filtrate is then added rapidly to 'a stirredaolutionof about 5 gms. of l-(tetraacetyld-ribitylamino)-4,5-dimethyl-benzene m125 cc. of acetic acid. After the-addition, the mixture is kept at about0-5" C. for approximately four hours, and then at room temperature forabout ten hours. At the beginning, a red, gummy, material separates andgradually hardens. Ihe 1- (tetraacetyl-d-ribitylat'nino)-2-p-nitrophenylazo-v aryldiazonium-halide is reacted withl-ribitylqamino-4,5-dimethyl benzene to produce al-ribitylamino-2-arylazo-4,5-dimethyl benzene or al-ribitylamino-2-para-substituted arylazo 4,5-1

dimethyl benzene.

X is halogen, R is an aryl group, and R is ribityl ortetrsacetylribityl.

\ The following examples illustrate methods oi carrying out the presentinvention, but it is to be understood that these examples are providediggfiway oiiliustration, and not by way 01' limi- Esample 1" NHR NrONO:,e

j an ribityi-ortetraaeetylrlbityl. I

About 3.34 gins. oi p-nitroaniline hydrochlo ride are dissolved bwarming in a solution oi approximately 3 cc. of concentratedhydrochlmrigacid in'about 3 cc. of water. The hot solution is addedto about 60cc. of water with stirring,

' and the mixture is then cooled toa roximately 10 C. At thistemperature, with stirring, about 4,5-dimethyl benzene,\ which is of adeep red color, is filtered, washed well with water, and dried. Itiscrystallized by dissolving in a small amount of hot chloroform anddiluting with hot methanol. Yield about 6.3 having a melt- About 1.31gm. of benzidine are dissolved in 25 cc. of :water containingapproximately 4.2 cc. concentrated hydrochloric acid. The mixture iscooled to about 0" C., and approximately 0.99 gm.

of sodium nitrite in about 10 cc. water are added.

Themixture is-cooied to 0-5 C., and about 4 gm. ofl-N-tetraacetylribitylamino-4,5-dimethy1- benzene in 8 cc. oi glacialacetic acid areadded. The deep purple. mixture is stirred for about 2hours, and then a 5% solution of sodium acetate is added 'dropwise untilthe mixture is faintly gray to Congo red paper. A gummy materialseparates which soon hardens. The mixture is stirred at 0-5 C. for fourhours longer, and then at room temperature for 12 hours. The solid 4,4,-

di-( 1 -tetraacetyl-d-ribitylamino4,5-dimethyl zphenylazo) diphenyl is.illtered, and washedwith water. Weight, 4.8 81118., melting point82-'85 C.

R is ribityl or tetraacetylribityl.

About 1.22 gm. of p-aminoben'zoic acid, 25 cc. of water and about 2 cc.of concentrated hydrochloric acid are heated to form a solution. Themixture is then cooled to -2 C., and a solution T of. about 0.62 gm. ofsodium nitrite in 15 cc. of

water is added slowly. After all the nitrous acid is used, the mixtureis added withstirring to a solution of about 3 gm. oil-N-tetraacetylribitylamino-4,5-dimethyl-benzene in '75 cc. acetic acidat approximately 0-5 C. The mixture, which turns dark purple, is stirredfor about two hours. and then a solution of 15 ms. of sodium acetate in45 cc. of water is added dropwise, whereupon the mixture becomes brightred, and a gummy material separates and gradually solidifies. The

.1 -N-(tetraacetyl-d-ribitylamino) 2 -p-carboxyphenylazo-4,5-dimethylbenzene is filtered, washed with water, and dried. This material meltsat 178-180 C.

Example 4 Hi0 NHR 1C1 HsC NHR HCI HaC HsC R. is ribityl ortetraacetylribityl.

About cc. of an aqueous solution of benzene diazonium chloride, preparedby diazotizing about 0.36 g. of aniline in the conventional manner, isadded at Iii- C. to a cold solutionp! about 1 g. oi.1-tetraacetylribitylamino-4,5-dimethyl benzene in approximately 25 cc.of glacial acetic acid. The mixture 'is stirreddor about an hour at10-15 C. during which time the solution becomes dark.

red and 1-tetraacetylribitylamino-2-phenylazo- 4,5-dimethyl benzeneseparates as a gummy mass, suitable for use as an intermediate in thesynthesisoi riboflavin without im-ther purification.

' Example 5 men I c mm N0:

I N02 I on a NOi' BCl C N= N0;

R is tetraacetylribityl.

About 2.8 gm. sodium nitrite are added with continuous stirring to 60cc. conc. sulfuric acid causing the temperature of the mixture to riseabout 225 cc. of glacial acetic acid. The resultin; deep purple-blackreaction mixture is stirred at about 0-5' C. for approximately 4 hoursand then at room temperature overnight. A blackbrown solid separates andis filtered and washed with water.

The solid, after recrystallized from acetone, yields deep purplecrystals melting at 175-8 C.

The 1 tetraacetylribitylamino 4,5 dimethyl benzene mentioned in theforegoing examples can be prepared by reacting xylidine withtetraacetylribonic acid nitrile in the presence of by drogen and ahydrogenation catalyst such as palladium, platinum, and nickel.

It will be understood that if desired the tetraacetylribityl compoundsabove mentioned can be replaced with the corresponding ribityl compoundsin equivalent proportions. Other parasubstituted anilines can be used inthe preparation of the diazonium compound instead of those abovementioned.

Other diazonium halides such as bromides or iodides can be used insteadof chlorides in the process above described.

This case is a continuation-in-part of applications Serial No. 398,584,flied June 18, 1941, and Serial No. 417,136 ,flled October 30, 1941, bythe same inventors, entitled respectively Chemical compounds andprocesses of preparing the same and Alloxazines and isoalloxazinesand'processes for their production.

Modifications may be made in carrying out the present invention, withoutdeparting irom the spirit and scope thereof, and the invention is to belimited only by the appended claims.

What is claimed is:

'1. 1 tetraacylribitylamino- 2 -arylazo- 4,5 -di- 7 methyl benzene.

4. 1 -tetraacetyl-d-ribitylamino- 2 -phenylazo- 4,5-dimethyl benzene.

5. 1-tetraa.cylribitylamino-2-p-nitrophenylazo- 4,5-dimethyl benzene.

6. 1 -(tetraacetyld -ribitylamino) 2 -p-nitr0- -phenylazo-4,5-dimethylbenzene.

its

7. 1 N -(tetraacylribitylamino) '2 -p-carboxyphenylazo-4,5-dimethy1benzene.

8. 1 -N- (tetraacetyl-d-ribitylamino) 2 -p-carboxyphenylsso-4,5-dimethylbenzene.

9. The process that comprises condensing an 'aryldiazonium-halide with atetraa cyl ribitylamino xylene. 5

10. The process aryldiazonium-halide yithl-tetraacylribitylamino-4z5-dimethyl benzene.

to about'4045 C. The resulting clear, pale'yellow solution is cooled toabout 30 C. and approximately 7.2 gm. of 2,4-dinitroaniline' are addedslowly. T e solution is cooled to about 20 0., stirred for 2 hours, andthen poured upon ice. The resulting clear, pale yellow solution is thenrapidly added to a. chilled solution of about 16.6 gms. oitetraacetylribityl xylidine dissolved in 11. The process thatcomprisescon'densinz on aryldiazonium-halide withl-tetraacetylribitylamino-4,5-dimethyl benzene.

12. The process that comprises condensin: a p-nitrophenyldismnium-halidewith atetrsscyl ribitylamino Xylene.

13. The process thit comprises condensing a'p-nitrophenyldiasonium-hslide with a ten-ascetylribitylamino xylene.

14."I'heprocess that comprises condensing ap-carboxylic-acid-phenyl-dissonium-hallde withatetraacylribitylaminoxylene.

that comprises condensing an

